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• W2006740966 abstract "It has been known for decades that a fraction of neuronal tubulin is insoluble in cold and also resistant to calcium as well as drugs that depolymerize microtubules. In this issue of Neuron, Song et al., 2013Song Y. Kirkpatrick L.L. Schilling A.B. Helseth D.L. Chabot N. Keillor J.W. Johnson G.V.W. Brady S.T. Neuron. 2013; 78 (this issue): 109-123Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar suggest that this unusual stability results from the polyamination of tubulin by transglutaminase. It has been known for decades that a fraction of neuronal tubulin is insoluble in cold and also resistant to calcium as well as drugs that depolymerize microtubules. In this issue of Neuron, Song et al., 2013Song Y. Kirkpatrick L.L. Schilling A.B. Helseth D.L. Chabot N. Keillor J.W. Johnson G.V.W. Brady S.T. Neuron. 2013; 78 (this issue): 109-123Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar suggest that this unusual stability results from the polyamination of tubulin by transglutaminase. For years, it was routine that each new generation of microtubule researchers would learn to make tubulin preps from bovine or porcine brain (Miller and Wilson, 2010Miller H.P. Wilson L. Methods Cell Biol. 2010; 95: 3-15PubMed Google Scholar). This would involve regular trips to a slaughterhouse, waiting for the brains to become available so that they could immediately be put on ice and rushed back to the lab, minced, and then put into a blender with cold buffer. From there, the strategy was based on the simple principle that microtubules would disassemble into soluble tubulin in the cold and reassemble into microtubules when the prep was warmed. Through cycles of warming and cooling, the prep would become progressively more enriched for tubulin. For most microtubule labs, those days are gone, because molecular approaches can now accomplish what used to require this tedious procedure. Reminiscing about those earlier days brings to mind a fundamental issue about tubulin and microtubules. The initial huge pellet produced by spinning down the brain homogenate was normally washed down the drain without further consideration—but this pellet actually contained a significant amount of tubulin that was not soluble in the cold. Although this was long known, the cold-stable tubulin fraction was given little attention by most investigators—one notable exception being Scott Brady. Nearly three decades ago, Brady et al., 1984Brady S.T. Tytell M. Lasek R.J. J. Cell Biol. 1984; 99: 1716-1724Crossref PubMed Scopus (118) Google Scholar compared the biochemical properties of tubulin in the cold-stable fraction with the properties of the temperature-cycled tubulin. Much of the tubulin in the cold-stable fraction was shown to be extremely basic in charge, as assessed by two-dimensional electrophoresis. Not only was this different from the cycling tubulin, but, for the ensuing decades, no tubulin isoform produced by any tubulin gene or posttranslational modification became apparent that could explain this behavior. From biochemical studies alone, it was impossible to know if the cold-insoluble tubulin represented a physiological structure or some artifact of the preparation. Brady et al., 1984Brady S.T. Tytell M. Lasek R.J. J. Cell Biol. 1984; 99: 1716-1724Crossref PubMed Scopus (118) Google Scholar proposed that cold-stable tubulin exists as regions of longer microtubules that are otherwise less stable, and subsequent electron microscopic work provided support for this idea (Heidemann et al., 1984Heidemann S.R. Hamborg M.A. Thomas S.J. Song B. Lindley S. Chu D. J. Cell Biol. 1984; 99: 1289-1295Crossref PubMed Scopus (40) Google Scholar; Sahenk and Brady, 1987Sahenk Z. Brady S.T. Cell Motil. Cytoskeleton. 1987; 8: 155-164Crossref PubMed Scopus (46) Google Scholar). Notably, cold stability is not an issue in terms of function, because vertebrate neurons would likely never be challenged with temperatures as cold as an ice bath. Rather, cold stability corresponds to resistance to depolymerization, the microtubule regions being composed of cold-stable tubulin that is resistant to virtually anything else that would normally cause microtubules to disassemble, including calcium, dilution, or exposure to drugs such as nocodazole. The hypothesis was that an especially stable tubulin fraction would serve to preserve the organization of the microtubule array, acting as nucleating elements to ensure that assembly occurred from pre-existing microtubules rather than occurring haphazardly (Brady et al., 1984Brady S.T. Tytell M. Lasek R.J. J. Cell Biol. 1984; 99: 1716-1724Crossref PubMed Scopus (118) Google Scholar; Black et al., 1984Black M.M. Cochran J.M. Kurdyla J.T. Brain Res. 1984; 295: 255-263Crossref PubMed Scopus (51) Google Scholar; Heidemann et al., 1984Heidemann S.R. Hamborg M.A. Thomas S.J. Song B. Lindley S. Chu D. J. Cell Biol. 1984; 99: 1289-1295Crossref PubMed Scopus (40) Google Scholar; Sahenk and Brady, 1987Sahenk Z. Brady S.T. Cell Motil. Cytoskeleton. 1987; 8: 155-164Crossref PubMed Scopus (46) Google Scholar). In addition, a marked increase in the levels of cold-stable tubulin as neurons mature was posited to contribute to a normal decline in morphological plasticity that occurs as axons achieve their adult wiring. While the mystery of the cold-stable fraction remained on the back burner for years, the general idea of stable microtubules acting as nucleating elements in the axon became popular. In cultured neurons from newborn and embryonic animals, it was shown that axons contain two sizable populations of microtubules that depolymerize at markedly different rates when exposed to drugs such as nocodazole (Baas and Black, 1990Baas P.W. Black M.M. J. Cell Biol. 1990; 111: 495-509Crossref PubMed Scopus (284) Google Scholar). These two populations, termed stable and labile, were shown to exist as two distinct domains on individual microtubules; the stable domain being toward the minus end of the microtubule and the labile domain being toward the plus end (Baas and Black, 1990Baas P.W. Black M.M. J. Cell Biol. 1990; 111: 495-509Crossref PubMed Scopus (284) Google Scholar; Brown et al., 1993Brown A. Li Y. Slaughter T. Black M.M. J. Cell Sci. 1993; 104: 339-352PubMed Google Scholar). In drug recovery experiments, it was shown that the labile domains assembled exclusively from the plus ends of the stable microtubules (Baas and Ahmad, 1992Baas P.W. Ahmad F.J. J. Cell Biol. 1992; 116: 1231-1241Crossref PubMed Scopus (88) Google Scholar). All of this was good proof of principle in favor of the functional hypothesis advocated by Brady and others, but the relatively stable microtubules in these cultured neurons were not synonymous with the unusually stable microtubules identified in Brady’s studies. The relatively stable microtubules in cultured neurons still depolymerized (albeit at a slower rate) in response to drugs, still turned over subunits with the soluble pool as evidenced by incorporation of ectopically expressed tagged tubulins, and did not display the unusual electrophoretic properties of Brady’s cold-stable tubulin. Moreover, Black et al., 1984Black M.M. Cochran J.M. Kurdyla J.T. Brain Res. 1984; 295: 255-263Crossref PubMed Scopus (51) Google Scholar documented that only about 6% of the tubulin is resistant to cold and calcium when these cultured neurons are homogenized. These observations suggest that neurons contain multiple classes of microtubule polymers that differ in stability. The relatively stable class is presumably rendered less dynamic by cofactors such as STOP and other microtubule-related proteins that function in this manner in other cell types (Slaughter and Black, 2003Slaughter T. Black M.M. J. Neurocytol. 2003; 32: 399-413Crossref PubMed Scopus (28) Google Scholar), whereas the most stable class is unique to neurons and rendered completely nondynamic by a modification of the tubulin itself. Brady’s group has now made significant progress toward solving the mystery of the modification that accounts for the unique properties of cold-stable tubulin. In their new article, they argue that the relevant modification is transglutaminase-catalyzed polyamination (Song et al., 2013Song Y. Kirkpatrick L.L. Schilling A.B. Helseth D.L. Chabot N. Keillor J.W. Johnson G.V.W. Brady S.T. Neuron. 2013; 78 (this issue): 109-123Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). This makes sense because polyamination is known to make proteins more basic, whereas most modifications make proteins more acidic or are neutral, and because polyamination is known to cause proteins to become stable, insoluble, and resistant to proteolysis. In addition, transglutaminase activity is known to increase as neurons mature. However, to date, there has been no evidence showing that brain tubulin is a substrate for this modification that may change microtubule stability. In the new article, Song et al., 2013Song Y. Kirkpatrick L.L. Schilling A.B. Helseth D.L. Chabot N. Keillor J.W. Johnson G.V.W. Brady S.T. Neuron. 2013; 78 (this issue): 109-123Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar report eight independent lines of biochemical evidence favoring the view that the polyamination of tubulin by transglutaminase contributes to the stabilization of microtubules in neurons. This is fascinating in that the more commonly studied tubulin modifications (acetylation and detyrosination) do not confer stability to microtubules but, rather, accumulate on microtubules that are more stable (Janke and Bulinski, 2011Janke C. Bulinski J.C. Nat. Rev. Mol. Cell Biol. 2011; 12: 773-786Crossref PubMed Scopus (616) Google Scholar). Thus, polyamination by transglutaminase would be the first identified modification that not only directly confers stability to microtubules but also makes them unusually stable in comparison to other stability classes of microtubules. Song et al., 2013Song Y. Kirkpatrick L.L. Schilling A.B. Helseth D.L. Chabot N. Keillor J.W. Johnson G.V.W. Brady S.T. Neuron. 2013; 78 (this issue): 109-123Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar present a model in which they posit that the polyamination step can occur on free tubulin, after which modified and unmodified tubulins intermingle during microtubule assembly. Additional modifications may occur on polymerized tubulin. This raises several questions. If the polyaminated tubulin is freely able to incorporate into any newly assembled microtubule polymer, how does a cold-stable fraction become distinguished from a cold-labile fraction? Is there a threshold level that must be incorporated to confer stability? Is the polyaminated tubulin distributed throughout a cold-stable microtubule, or does the polyaminated tubulin simply have to flank otherwise labile regions to make those regions stable as well? Is there any spatial or temporal regulation over the polyamination of tubulin that influences its pattern of incorporation into microtubules? These new findings on cold-stable microtubules might also have implications for another great mystery of the axonal microtubule array—the nature of microtubule transport. Brady has long favored the idea that the cold-stable regions along axonal microtubules act as “transportable microtubule organizing complexes” (Brady et al., 1984Brady S.T. Tytell M. Lasek R.J. J. Cell Biol. 1984; 99: 1716-1724Crossref PubMed Scopus (118) Google Scholar; Sahenk and Brady, 1987Sahenk Z. Brady S.T. Cell Motil. Cytoskeleton. 1987; 8: 155-164Crossref PubMed Scopus (46) Google Scholar). Interestingly, after years of controversy over whether or not axonal microtubules actually move, live-cell imaging on cultured neurons finally revealed that, in the axons of cultured neurons, microtubules unquestionably do move down the axon, but they do so only as very short fragments (Wang and Brown, 2002Wang L. Brown A. Curr. Biol. 2002; 12: 1496-1501Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). Curiously, these mobile microtubules are not only very short, but they are also very stable, undergoing no detectable length changes during bouts of imaging. Mechanistic considerations are most consistent with these short microtubules moving by a sliding filament mechanism rather than as cargo, which is to say that the motor domain of the relevant molecular motor interacts with the short mobile microtubule, whereas the cargo domain interacts with a longer stationary microtubule (Baas and Mozgova, 2012Baas P.W. Mozgova O.I. Cytoskeleton (Hoboken). 2012; 69: 416-425Crossref PubMed Scopus (30) Google Scholar). One possibility is that, when a microtubule is thoroughly chopped by a microtubule-severing protein, what remains are the most stable regions of the microtubule—those enriched with polyaminated tubulin. It may be that it is the unique biochemical properties of polyaminated tubulin that not only provide for great stability of these fragments but also explain how certain motor proteins recognize them and how those motors know to transport them via a sliding filament mechanism. If this is the case, one could also imagine that a much longer microtubule in an adult axon may contain multiple regions that are rich in polyaminated tubulin, thus enabling greater interaction with the relevant motor proteins. If this is the case, perhaps microtubules do not need to be so short in order to be transported in adult axons (Figure 1). Clearly, there are many issues left on the table, but the latest work by Brady’s group has, after nearly three decades, made a much-needed leap toward understanding the nature of the cold-stable tubulin fraction. With rapid progress now underway, it is with some melancholy that many researchers will now remember washing that first pellet down the drain. Transglutaminase and Polyamination of Tubulin: Posttranslational Modification for Stabilizing Axonal MicrotubulesSong et al.NeuronApril 10, 2013In BriefSong et al. expand the repertoire of tubulin posttranslational modifications by discovering that neuronal tubulin can be polyaminated by transglutaminase. Tubulin polyamination stabilizes axonal microtubules and may contribute to the regulation of neurite differentiation and maturation of axonal connections. Full-Text PDF Open Archive" @default.
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• W2006740966 title "Microtubule Stability in the Axon: New Answers to an Old Mystery" @default.
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